Novel Genomic Variants, Atypical Phenotypes and Evidence of a Digenic/Oligogenic Contribution to Disorders/Differences of Sex Development in a Large North African Cohort

Abstract

In a majority of individuals with disorders/differences of sex development (DSD) a genetic etiology is often elusive. However, new genes causing DSD are routinely reported and using the unbiased genomic approaches, such as whole exome sequencing (WES) should result in an increased diagnostic yield. Here, we performed WES on a large cohort of 125 individuals all of Algerian origin, who presented with a wide range of DSD phenotypes. The study excluded individuals with congenital adrenal hypoplasia (CAH) or chromosomal DSD. Parental consanguinity was reported in 36% of individuals. The genetic etiology was established in 49.6% (62/125) individuals of the total cohort, which includes 42.2% (35/83) of 46, XY non-syndromic DSD and 69.2% (27/39) of 46, XY syndromic DSD. No pathogenic variants were identified in the 46, XX DSD cases (0/3). Variants in the AR, HSD17B3, NR5A1 and SRD5A2 genes were the most common causes of DSD. Other variants were identified in genes associated with congenital hypogonadotropic hypogonadism (CHH), including the CHD7 and PROKR2. Previously unreported pathogenic/likely pathogenic variants (n = 30) involving 25 different genes were identified in 22.4% of the cohort. Remarkably 11.5% of the 46, XY DSD group carried variants classified as pathogenic/likely pathogenic variant in more than one gene known to cause DSD. The data indicates that variants in PLXNA3, a candidate CHH gene, is unlikely to be involved in CHH. The data also suggest that NR2F2 variants may cause 46, XY DSD.

TheNR5A1/SF-1variant p.Gly146Ala cannot explain the phenotype of individuals with a difference of sex development

“…The variant in GLI2 (c.3528G>T; p.Gln1176His) was rated as pathogenic by most of the in silico prediction tools and variants in additional genes were rated as VUS when analyzing according to pathogenicity guidelines. Variants in GLI2 have been described in syndromic DSD patients together with short stature, primary hypogonadism, heart and craniofacial anomalies and 46,XY gonadal dysgenesis (42), as well as in 46,XY non-syndromic DSD manifesting with female external genitalia or with ambiguous genitalia (23, 43, 44). Variants in CHD7 have been previously associated with a broad range of 46,XY DSD phenotypes, including males with hypospadias or micropenis and individuals with female external genitalia (27, 45).…”

“…SOX8 gene variants are associated with a range of phenotypes including 46,XY DSD and human reproductive anomalies in males and females (62). Single-nucleotide variants (SNV) associated with 46,XY gonadal dysgenesis are mostly located in the HMG-box of SOX8 (43), while those reported in infertile patients flank the HMG-box or localize to one of the transactivation domains (TA) (62). However, more recently, a missense variant in the TA2 region of SOX8 was identified in a 46,XY patient with gonadal dysgenesis (43).…”

“…Single-nucleotide variants (SNV) associated with 46,XY gonadal dysgenesis are mostly located in the HMG-box of SOX8 (43), while those reported in infertile patients flank the HMG-box or localize to one of the transactivation domains (TA) (62). However, more recently, a missense variant in the TA2 region of SOX8 was identified in a 46,XY patient with gonadal dysgenesis (43). The novel c.676A>C; p.Thr226Pro variant is located in the first TA of the protein.…”

Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development

“…One possible explanation for this phenotypic variability is digenic or oligogenic inheritance. In 46,XY DSD patients with variants in NR5A1 , additional variants that potentially modify phenotypes have been identified in at least 37 genes [ 35 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. Digenic inheritances are the simplest among the digenic/oligogenic inheritances and have occasionally been identified in a manner similar to the Mendelian inheritance [ 67 ].…”

“…Digenic inheritances are the simplest among the digenic/oligogenic inheritances and have occasionally been identified in a manner similar to the Mendelian inheritance [ 67 ]. Among the 37 genes mentioned above, genes that potentially contribute to digenic inheritances in combination with NR5A1 include AMH , AR , FLRT3 , INHA , MAP3K1 , SOX3 , STAR , SRY , and ZFPM2 [ 35 , 61 , 62 , 63 , 64 , 65 , 66 ]. In many cases of digenic inheritance, proteins encoded by the two genes have protein-protein interactions [ 68 ].…”